====== Diffuse astrocytoma IDH Mutant outcome ======

The [[WHO classification]] for [[IDH-mutant]] grade II and grade III [[astrocytoma]] may not be as prognostically meaningful as expected.

Liu et al. aimed to develop a novel classification system based on the DNA damage response signature.

They developed the [[gene signature]] of DNA damage response with 115 samples from The [[Cancer Genome Atlas]] (TCGA) database. The dataset from [[Chinese Glioma Genome Atlas]] (CGGA) database with 41 samples was used as the validation set. Lasso Cox regression model was applied for selection of the best signature. Gene set enrichment analysis (GSEA) and gene ontology (GO) analysis were implemented to reveal its biological phenotype.

A two-gene DNA damage response signature (RAD18, MSH2) was developed using the lasso Cox regression model based on the TCGA dataset. Its prognostic efficiency was validated in the CGGA cohort. The result of the [[Cox regression]] [[analysis]] showed that the signature has better predictive accuracy than the WHO grade. The risk score was an independent prognostic factor for the overall survival of the IDH-mutant grade II and grade III astrocytoma. GSEA and GO analysis confirmed enhanced processes related to DNA damage response in high-risk group.

They developed a two-gene signature that can effectively predict the prognosis of patients with IDH-mutant grade II and grade III astrocytoma. It suggests a novel classification of astrocytoma with better prognostic accuracy based on the expression of DNA damage response genes
((Liu Q, Wang K, Huang R, Tong X, Jiang T, Wang J, Yang P. A novel DNA damage
response signature of IDH-mutant grade II and grade III astrocytoma at
transcriptional level. J Cancer Res Clin Oncol. 2020 Feb 14. doi:
10.1007/s00432-020-03132-x. [Epub ahead of print] PubMed PMID: 32060643.
)).


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A cohort with known IDH-mutations demonstrated a median survival of 10.9 years
((Reuss DE, Mamatjan Y, Schrimpf D, et al. IDH mutant diffuse and anaplastic astrocytomas have similar age at presentation and little difference in survival: a grading problem for WHO. Acta Neuropathol. 2015; 129:867–873)).

Pre-IDH era data showed worse prognosis with the following
((Pignatti F, van den Bent M, Curran D, et al. Prognostic factors for survival in adult patients with cerebral low-grade glioma. J Clin Oncol. 2002; 20:2076–2084)) 
(will now need to be validated with known IDH status):

1. age > 40 years (perhaps the most important unfavorable prognosticator)

2. astrocytoma histology

3. largest tumor diameter ≥ 6 cm

4. tumor crossing the midline

5. neurologic deficit prior to surgery

==== Dedifferentiation ====

These tumors are capable of malignant dedifferentiation, and the ultimate behavior of these tumors in adults is usually not benign, as 75% of adult tumors undergo anaplastic progression into IDH-mutant [[anaplastic astrocytoma]] and thence IDH-mutant glioblastoma, which is the major cause of morbidity, whereas pediatric diffuse astrocytomas (age<20) rarely undergo malignant degeneration
((Broniscer A, Baker SJ, West AN, et al. Clinical and molecular characteristics of malignant transforma- tion of low-grade glioma in children. J Clin Oncol. 2007; 25:682–689)).

WHO grade II astrocytomas tend to undergo malignant transformation more quickly when diagnosed after age 45 years. Once dedifferentiation occurs, median survival is 2–3 years beyond that event (pre-IDH era data
((Shafqat S, Hedley-Whyte ET, Henson JW. Age-
Dependent Rate of Anaplastic Transformation in 
Low-Grade Astrocytoma. Neurology. 1999; 52:
867–869))).

The UCSF preoperative grading system for WHO grade II astrocytomas
((Chang EF, Smith JS, Chang SM, et al. Preoperative
prognostic classification system for hemispheric low-grade gliomas in adults. J Neurosurg. 2008; 109:817–824))
assigns 1 point for the presence of each of the 4 parameters shown:


{{::preoperative_grading_of_who_grade_ii_astrocytomasa.png?600|}} 

The points are summed and the prognosis is 

{{::preoperative_grading_of_who_grade_ii_astrocytomasb.png?600|}}

(this scale has been validated at other institutions,
((Chang EF, Clark A, Jensen RL, et al. Multiinstitutional validation of the University of California at San Francisco Low-Grade Glioma Prognostic Scoring System. Clinical article. J Neurosurg. 2009; 111:203–210))
but uses pre-IDH era data and will need to be updated).